The present invention relates to an improvement in the process for making antitumor antibiotic duocarmycin prodrugs. Such prodrugs can be used for selective treatment of cancer through antibody-directed enzyme prodrug therapy (ADEPT). The compounds are based on the cytotoxic antibiotics (+)-CC-1065, (+)-Duocarmycin A and (+)-Duocarmycin SA.
CC-1065 and duocarmycin analogues, which typically consist of a DNA-alkylating and a DNA-binding part, are known for their potent antitumor properties, but are normally not used on their own because of their extreme high toxicity. Nowadays they are being explored as cytotoxic drugs in antibody-drug conjugates (ADCs).
ADCs seem to have the potential to address the great unmet need for effective new treatments in cancer, which continues to be a major cause of death, by directing the highly potent cytotoxic drug specifically to cancer cells. Therefore, an industrial scale synthesis of duocarmycin prodrugs is one of the key aspects for the future commercial success of ADCs comprising duocarmycin analogues.
Various processes for making duocarmycin analogues and their intermediates, in particular for making the DNA-alkylating part of such analogues, are known in the prior art.
L. F. Tietze et al. in Chem. Eur. J. 2008, 14, 895-901 describe the enantio- and diastereoselective synthesis of duocarmycin-based prodrugs by epoxide opening. For the metal-mediated cyclisation of compound (1) to give compound (2) several different reaction conditions to give reasonable results had to be explored.

To achieve a stereoselective reaction, the authors concentrated on the use of lithium-containing cuprates as it was known that lithium tends to coordinate to the oxygen of the epoxide to allow the formation of a sterically fixed transition state, which is shown in Scheme 5 of said reference. The best results for the cyclisation reaction were achieved by using the copper organyl Li2Cu(CN)Me2 (78% yield) and the zinc organyl Li2Zn(SCN)Me3 (72% yield), whereas employing n-BuLi nearly exclusively afforded (47% yield) the dehalogenated product with only 7% of the desired five-membered ring product (2). See Table 2 in said reference.
L. F. Tietze et al. describe in Schemes 6 and 7 of the Eur. J. Org. Chem. 2010, 6909-6921 a metal-induced ring-closure of the epoxide tert-butyl (8-cyano-4-(benzyloxy)-1-bromo-naphthalen-2-yl)(oxiran-2-yl)carbamate to the desired enantiopure five-membered ring product using n-butyl lithium, but in a yield of only 12%. It is further mentioned that all other attempts to initiate the cyclisation via a zincate or cuprate failed.
Thus, while duocarmycin analogues and processes for making key intermediates of them are known in the prior art, there still exists a need for an improvement. In particular, it would be desirable to have an enantioselective process providing duocarmycin analogue intermediates in a good purity, acceptable yield and in a form which is well suitable for the next conversion steps into duocarmycin analogues having a DNA-alkylating part as well as a DNA-binding part and corresponding antibody-drug conjugates, which process does not require the use of intermetal reagents like the aforementioned expensive, hard-to-handle and not-readily-available lithium cuprates and -zincates.